The primary objectives of this research group has been to address key knowledge gaps in the effects of dioxin which have created uncertainty in human risk assessment. We have approached this by attempting to clarify the shape of the dose-response curve of dioxin in the low-dose region, by determining if animal models are appropriate for estimating human risks, and by developing sensitive and specific exposure markers and markers of susceptibility. Isolated cell systems, experimental rodent models, and human samples are used to address a number of issues that impact on risk assessment of dioxin and its structural analogs. The shape of the dose-response curve has been determined for the effects of dioxin in rat liver and lung by quantifying transcriptional activation of dioxin responsive genes and comparing responses to more complex biological effects such as cell proliferation and growth of preneoplastic lesions. Dose-response relationships were established for dioxin effects on CYP1A1, -1B1, and 1A2 enzymes, UPPG1 cell proliferation, growth of preneoplastic lesions, thyroid hyperplasia, cell specific changes in liver and reproductive tract, EGFR, TGF-alpha, thyroid hormones, steroid hormones, and the Ah receptor. These studies have established mechanistic links between various signal transduction pathways involved in dioxin's effects. Novel biologically-based models have been established for dioxin-induced changes in gene expression, liver cancer, and thyroid cancer. Lymphocytes have been isolated from human blood obtained from a North Carolina donor group. We have initiated studies to determine interindividual and interassay variability for a number of endpoints including CYP1A1, -1B1 and EROD. Changes in the gene expression of dioxin responsive genes is being measured by using a very sensitive reverse transcript PCR method. Human lymphocytes have also been obtained from groups exposed to dioxin either occupationally or environmentally. Studies are also underway to measure gene expression in these groups. Future plans are to continue developing models to predict the range of expected risks in the population based on dioxin clearance, the Ah receptor, changes in gene expression, effects on cell proliferation, chloracne, and cancer.